Pancreatic Enzyme Replacement Therapy for Pancreatic Exocrine Insufficiency in the 21St

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century
Tony Trang, Johanna Chan, David Y Graham
CITATION / Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century. World J Gastroenterol 2014; 20(33): 11467-11485
URL / http://www.wjgnet.com/1007-9327/full/v20/i33/11467.htm
DOI / http://dx.doi.org/10.3748/wjg.v20.i33.11467
OPEN ACCESS / Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.
CORE TIP / In the last two decades, a number of studies comparing pancreatic enzymes and placebo have confirmed that pancreatic enzymes are superior to placebo for treatment of pancreatic malabsorption. While many patients achieved a satisfactory clinical response, individualization is often needed. Studies conclusively show that dose escalation is not a reliable method of obtaining further improvements and instead results in increased costs. Here, we describe alternate strategies for obtaining a satisfactory clinical response including changing to, or adding, a different product, adding non-enteric coated enzymes, use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration.
KEY WORDS / Pancreatic insufficiency; Pancreatic enzyme replacement therapy; Lipase; Clinical trials; Steatorrhea; Fat malabsorption; Chronic pancreatitis
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NAME OF JOURNAL / World Journal of Gastroenterology
ISSN / 1007-9327 (print) 2219-2840 (online)
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Name of journal: World Journal of Gastroenterology

ESPS Manuscript NO: 12193

Columns: FRONTIER

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century

Tony Trang, Johanna Chan, David Y Graham

Tony Trang, Johanna Chan, David Y Graham, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, United States

Author contributions: Trang T, Chan J and Graham DY have been involved equally and have read and approved the final manuscript; Trang T, Chan J and Graham DY meet the criteria for authorship established by the International Committee of Medical Journal Editors and verify the validity of the results reported.

Supported by The Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grants No. DK067366 and No. DK56338 which funds the Texas Medical Center Digestive Diseases Center

Correspondence to: David Y Graham, MD, Professor, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, 2002 Holcombe Blvd, Houston, TX 77030, United States.

Telephone: +1-713-7950232 Fax: +1-713-7901040

Received: June 26, 2014 Revised: July 21, 2014 Accepted: July 29, 2014

Published online: September 7, 2014

Abstract

Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes, (e.g., giving unprotected enzymes at the start of the meal and acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy.

© 2014 Baishideng Publishing Group Inc. All rights reserved.

Key words: Pancreatic insufficiency; Pancreatic enzyme replacement therapy; Lipase; Clinical trials; Steatorrhea; Fat malabsorption; Chronic pancreatitis

Core tip: In the last two decades, a number of studies comparing pancreatic enzymes and placebo have confirmed that pancreatic enzymes are superior to placebo for treatment of pancreatic malabsorption. While many patients achieved a satisfactory clinical response, individualization is often needed. Studies conclusively show that dose escalation is not a reliable method of obtaining further improvements and instead results in increased costs. Here, we describe alternate strategies for obtaining a satisfactory clinical response including changing to, or adding, a different product, adding non-enteric coated enzymes, use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration.

Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century. World J Gastroenterol 2014; 20(33): 11467-11485 Available from: URL: http://www.wjgnet.com/1007-9327/full/v20/i33/11467.htm DOI: http://dx.doi.org/10.3748/wjg.v20.i33.11467

BIOGRAPHY

David Y Graham (Figure 1), MD is a Professor in the Departments of Medicine and Molecular Virology and Microbiology at Baylor College of Medicine, in Houston, TX. He received his undergraduate degree from the University of Notre Dame in South Bend, Indiana, his MD degree with honor from Baylor University College of Medicine in 1966. He board certified in Medicine and Gastroenterology. Dr. Graham is a Past President of the American College of Gastroenterology. He is the Editor of the journal Helicobacter. His primary interests are related to infections of the gastrointestinal tract tract including Helicobacter pylori, Norovirus infections, and the infectious etiology of inflammatory bowel disease.

Dr. Graham is internationally recognized for his expertise in medicine and gastroenterology and is the author of more than 900 scientific papers, several books, and more than 100 chapters in medical text books. One of his papers is listed as one of the three most important papers in gastroenterology in the first 80 years of the Annals of Internal Medicine: (i.e., Landmark Papers in Internal Medicine: The First 80 Years of Annals of Internal Medicine. Harold C Sox and Edward J Huth (Eds), 2009 (paper cited: Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992; 116: 705-8.).

He is a Master of the American College of Gastroenterology and a Fellow of the American College of Physicians, the American Academy of Microbiology, the American Association for the Advancement of Science, the Infectious Diseases Society of America, and World Innovation Foundation. He is a past president of the American College of Gastroenterology and the winner of many prestigious awards. He previously was a physician to NASA astronauts during the Apollo program. He is listed as among the Top 50 Most Influential Gastroenterology Professionals of the 20th Century by Gastroenterology.com, as one of ISI’s Highly Cited Researcher in Clinical Medicine, and as one of the Best Doctors in America. He has patents regarding development of diagnostic tests for Helicobacter pylori infection, the cause of peptic ulcer and gastric cancer and for vaccine development of Norwalk virus infection, the most common cause of food borne and cruse ship associated diarrhea.

INTRODUCTION

Orally administered pancreatic enzymes have been available since at least the 19th century, when many formulations were available as digestive aids. At that time it was known that orally administered enzymes were destroyed in gastric juice and that they were most effective when given in alkaline media[1]. A review of early 20th century research on the use of pancreatic enzymes for treatment of steatorrhea secondary to exocrine pancreatic insufficiency reported a wide variation in efficacy, yielding an overall 50% approximate reduction in steatorrhea[2]. The goal of pancreatic enzyme therapy is to restore normal fat absorption by delivering “a sufficient amount of active lipase at the right place, i.e., duodenum and proximal jejunum, and at the right time, i.e., in parallel with gastric emptying of nutrients”[3]. Achieving this goal has remained elusive despite the introduction and use of modern potent enzyme preparations[3-9].

Normal fat absorption requires integration of nutrient delivery with pancreatic and biliary secretions to accomplish hydrolysis and solubilization of ingested fats and fat-soluble dietary constituents. The normal process is finely tuned and requires coordination of many steps including controlled delivery of nutrients to the intestine, neutralization of acidic gastric contents, and secretion of pancreatic enzymes and bile to promote optimal digestion and solubilization of digestive products. These products of digestion then require a sufficient luminal intestinal surface area for absorption. Normally, the intestinal tract is able to process and absorb approximately 95% of ingested fat. There is considerable reserve capacity with all of the elements such that major anatomic alterations are required for weight loss surgery to be effective. The pancreas provides the bulk of the lipase needed for hydrolysis of triglycerides as well as bicarbonate to neutralize the acidic gastric contents. Pancreatic steatorrhea generally does not occur until lipase secretion is reduced by 90% or more[10].

Pancreatic steatorrhea is caused by disruptions of the normal process in which pancreatic enzymes are either inactivated or are otherwise unavailable (e.g., blockage of the pancreatic duct, or resection or destruction of the glandular pancreas). Fungal, plant, and animal (especially porcine) pancreatic enzymes are available, and theoretically the simple addition of these enzymes with meals should resolve the deficiency and restore normal absorption. Despite this hypothetical possibility, the administration of large doses of replacement pancreatic enzymes generally has not resulted in complete restoration of normal fat absorption[2,9,11-14].

One early approach was the use of enteric coating to protect the enzymes during passage through the stomach, but this was met with limited success[2,15]. Subsequent studies of normal gastric and pancreatic physiology identified many other barriers to successful treatment with pancreatic enzymes[16,17] (Table 1). This paper discusses the current status and clinical effectiveness of pancreatic enzyme therapy as well as possible approaches to overcoming the barriers to successful therapy. We also discuss the many myths and common misconceptions regarding therapy (Table 2). We begin with a historical review of the use of pancreatic enzyme therapy in the treatment of malabsorption due to chronic pancreatitis and cystic fibrosis; this historical perspective also provides the physiologic basis for the use of supplemental pancreatic enzymes and adjuvant therapies. We focus on overcoming the limitations of common strategies used to improve outcome, such as increasing the amount of lipase per meal, use of enteric-coating, the timing of enzyme administration in relation to meals, and use of antacids and antisecretory drug as adjuvant therapy. Success requires a strategy that is targeted to identify and overcome the specific barriers preventing correction of steatorrhea (Table 1). Currently, many patients achieve a satisfactory clinical response but few experience complete normalization of fat absorption; more than half often require individualized therapy to obtain symptomatic and nutritional relief[3-8].

The review is based on understanding the underlying physiology and the results of clinical trials in patients. It does not seek to comprehensively review all studies but rather to illustrate key principles and to show consistency of the results (typically failures to achieve correction of steatorrhea). Although meta-analyses have confirmed that enzyme therapy is superior to placebo, there is no evidence that one product is superior to another or that any will reliably eliminate steatorrhea. We also do not consider potential alternate indications for pancreatic enzymes such as abdominal pain in patients with chronic pancreatitis[18] or irritable bowel syndrome[19,20].

MODERN ERA OF PANCREATIC ENZYME THERAPY

In 2004 the United States Food and Drug Administration (FDA) issued a requirement for manufacturers of prescription pancreatic enzyme products to submit new drug applications (NDAs) for all pancreatic enzyme products[21]. The FDA provided guidance on the minimal standards regarding the amount and stability of enzymes and the studies needed to establish efficacy (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071651.pdf). The companies were told that only products receiving a new FDA approval would be allowed to remain on the market by 2008; this was later extended to 2010. The primary efficacy requirement was based on the comparison of the active product with placebo, which set a relatively low bar for efficacy. The FDA also requested, but did not require for approval, additional information about each product in terms of studies addressing gastric emptying, mixing, and dissolution time. The majority of products now available in the United States are enteric coated and formulated as microbeads, microtablets or microspheres (we use the terms “microbeads”, “microtablets” and “microspheres” interchangeably). A non-enteric-coated product (Viokaze®, Forest Pharmaceuticals) was approved in 2012 (Table 3).

Most of the formulations are marketed in different strengths based on enzyme activity per capsule or tablet. Increasing the activity/dosage unit has generally been achieved by re-packaging the basic enzyme product into larger capsules, using different diameter enteric-coated beads, or both (Figure 2, Table 3).

The available prescription products are relatively expensive (Table 3). However, because “health food” stores still offer pancreatic enzymes as non-prescription “digestive aids” at a relatively low cost, many patients are likely to also use them. As noted, none of the currently available approved formulations have been shown to reliably achieve normal absorption irrespective of the quantity of lipase administered.

QUANTITY OF LIPASE REQUIRED TO ABOLISH STEATORRHEA

Normal pancreas

Normally, lipase is secreted early in the postprandial period and reaches a maximum within the first hour; the majority of fat digestion and absorption normally occurs within the proximal small intestine[22]. The ability to measure lipase activity led investigators to ask whether there was a best, appropriate, or minimum amount of lipase needed to correct steatorrhea. The available data are confusing in part because lipase units are often presented in different units, making direct comparisons difficult. Many basic and clinical studies use either international units (IU) or United States Pharmacopeia (USP) units. Commercial products in the United States are rated in USP units (1 IU = 3 USP units). We will provide the results whenever possible in USP units. When the units are not clear (as in some older papers) we will simply state the units as lipase units or provide the units name used for that study. The strength of current products ranges from 3000 USP units to 36000 USP units of lipase per dosage unit (e.g., per capsule) (corresponding to a range of 1000 to 12000 IU) (Table 3). The amount of postprandial lipase secreted under normal physiologic circumstances has been estimated at between 9000 to 18000 USP units/min[22,23] Measurements from a patient with a pancreatic fistula suggested that a 60 kg man would produce 192000 Cherry-Crandall units[24]. Overall, the results of such studies depend on the experimental methodology and may explain the wide variation noted[25]. As noted previously, the pancreas has a tremendous reserve capacity, and perfusion studies have suggested that approximately 5% of normal output is the threshold to maintain normal fat absorption[26]. Other studies report somewhat higher amounts[10,27].